Oral care product and methods of use and manufacture thereof

ABSTRACT

This invention relates to high-water oral care compositions comprising a basic amino acid or salt thereof, together with a precipitated calcium carbonate, glycerol, and to methods of using and of making these compositions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalApplication No. 62/825,939, filed on Mar. 29, 2019, the contents ofwhich are incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to high-water oral care compositions comprising abasic amino acid or salt thereof, together with a precipitated calciumcarbonate, glycerin, and to methods of using and of making thesecompositions.

BACKGROUND OF THE INVENTION

Arginine and other basic amino acids have been proposed for use in oralcare and are believed to have significant benefits in combating cavityformation and tooth sensitivity.

Commercially available arginine-based toothpaste, such as ProClude®toothpaste or DenClude® toothpaste, for example, contains argininebicarbonate and precipitated calcium carbonate, but not fluoride. Thecarbonate ion is believed to have cariostatic properties, and thecalcium is believed to form in complex with arginine to provide aprotective effect.

Precipitated calcium carbonate is more friable and less abrasive thannatural calcium carbonate for example, and this can result in lessdamaging abrasion to enamel, which is good for sensitive teeth.

Accordingly, there is a need for a stable oral care product thatcomprising a basic amino acid and beneficial minerals such as fluorideand calcium, which moreover has an optimized abrasive system to provideeffective cleaning without damaging abrasivity, particularly for peoplehaving sensitive teeth.

BRIEF SUMMARY OF THE INVENTION

The invention encompasses oral care compositions and methods of usingthe same that are believed to be effective in inhibiting or reducing theaccumulation of plaque, reducing levels of acid producing (cariogenic)bacteria, remineralizing teeth, and inhibiting or reducing gingivitis.The invention also encompasses compositions and methods to clean theoral cavity and provide improved methods of promoting oral health and/orsystemic health, including cardiovascular health, e.g., by reducingpotential for systemic infection via the oral tissues.

The invention thus comprises an oral care composition (Composition ofthe Invention), e.g., a dentifrice, comprising

-   -   i. an effective amount of a basic amino acid, in free or salt        form (e.g., arginine);    -   ii. an effective amount of a soluble fluoride salt, (e.g.,        sodium fluoride, stannous fluoride or sodium        monofluorophosphate, e.g., providing from about 100 to 25,000        ppm, e.g., about 750 to about 2000 ppm fluoride ions);    -   iii. an effective amount of precipitated calcium carbonate (PCC)        (e.g., having an average particle size of 1-15 microns, e.g.        2-10 microns, e.g. about 5 microns and water absorption of        greater than 15 g/100 g) (e.g., at about 10 wt. % to about 50        wt. %); and    -   iv. an effective amount of glycerin (e.g., from 0.1%-20% by wt)        (e.g., from 0.1%-7% by wt.) (e.g., from 15%-20% by wt)    -   wherein the composition comprises water in an amount of at least        30% by wt of the composition.

The composition is effective for cleaning and strengthening the teethwithout damaging abrasion, e.g., in persons with sensitive teeth, forexample has a good Pellicle Cleaning Ratio, e.g., at least 70, and a lowRadioactive Dentine Abrasivity value, e.g., less than 140.

In some embodiments, the formulation further comprises an anionicsurfactant, e.g., sodium lauryl sulfate; an anionic polymer, e.g., acopolymer of methyl vinyl ether and maleic anhydride; and/or anantibacterial agent.

In particular embodiments, the Compositions of the Invention are in theform of a dentifrice comprising additional ingredients selected from oneor more of water, abrasives, surfactants, foaming agents, vitamins,polymers, enzymes, additional humectants (e.g., humectant in addition toglycerin), thickeners, antimicrobial agents, preservatives, flavorings,colorings and/or combinations thereof.

Without intending to be bound by a particular theory, it is believedthat the presence of small particles in a formulation with arginine andcalcium may help plug the microtubules responsible for hypersensitiveteeth and help repair precarious lesions in the enamel and dentin.

It is moreover found that the combination of fluoride and a basic aminoacid, e.g., arginine, in an oral care product according to particularembodiments of the present invention produces unexpected benefits beyondand qualitatively different from what can be observed using compositionscomprising effective amounts of either compound separately, in promotingremineralization, repairing pre-carious lesions, and enhancing oralhealth. It has moreover been found that this action can be furtherenhanced by addition of a small particle abrasive comprising acombination of natural calcium carbonate and precipitated calciumcarbonate, which may act to help fill microfissures in the enamel andmicrotubules in the dentin.

The presence of a basic amino acid is also surprisingly found to reducebacterial adhesion to the tooth surface, particularly when the basicamino acid is provided in combination with an anionic surfactant. Thecombination of the basic amino acid and the anionic surfactant and/oranionic polymer e.g., PVM/MA also enhances delivery of antimicrobialagents, particularly triclosan.

The invention thus further encompasses methods to (i) reduce or inhibitformation of dental caries, (ii) reduce, repair or inhibit pre-cariouslesions of the enamel, e.g., as detected by quantitative light-inducedfluorescence (QLF) or electrical caries measurement (ECM), (iii) reduceor inhibit demineralization and promote remineralization of the teeth,(iv) reduce hypersensitivity of the teeth, (v) reduce or inhibitgingivitis, (vi) promote healing of sores or cuts in the mouth, (vii)reduce levels of acid producing bacteria, (viii) to increase relativelevels of arginolytic bacteria, (ix) inhibit microbial biofilm formationin the oral cavity, (x) raise and/or maintain plaque pH at levels of atleast pH about 5.5 following sugar challenge, (xi) reduce plaqueaccumulation, (xii) reduce dry mouth, (xiii) reduce erosion, (xiv)whiten the teeth, (xv) immunize or protect the teeth against cariogenicbacteria, (xvi) clean the teeth and oral cavity and/or (xvii) promotesystemic health, including cardiovascular health, e.g., by reducingpotential for systemic infection via the oral tissues, comprisingapplying a Composition of the Invention to the oral cavity, e.g., byapplying a Composition of the Invention to the oral cavity of a subjectin need thereof.

DETAILED DESCRIPTION OF THE INVENTION

General Description

The invention thus comprises an oral care composition (Composition 1.0)comprising

-   -   i. an effective amount of a basic amino acid, in free or salt        form (e.g., arginine);    -   ii. an effective amount of a soluble fluoride salt, e.g., sodium        fluoride, stannous fluoride or sodium monofluorophosphate, e.g.,        providing from about 100 to 25,000 ppm, e.g., about 750 to about        2000 ppm fluoride ions;    -   iii. an effective amount of precipitated calcium (e.g., about 30        wt. % to about 50 wt. %); and    -   iv. an effective amount of glycerin (e.g., from 0.1%-20% by wt)        (e.g., from 0.1%-7% by wt.) (e.g., from 15%-20% by wt)    -   wherein the composition comprises water in an amount of at least        30% by wt of the composition.        for example, any of the following compositions:        1.0.1. Composition 1.0 wherein the basic amino acid is arginine,        lysine, citrullene, ornithine, creatine, histidine,        diaminobutanoic acid, diaminoproprionic acid, salts thereof        and/or combinations thereof.        1.0.2. Composition 1.0 or 1.0.1 wherein the basic amino acid has        the L-configuration.        1.0.3. Any of the preceding compositions is provided in the form        of a salt of a di- or tri-peptide comprising the basic amino        acid.        1.0.4. Any of the preceding compositions wherein the basic amino        acid is arginine.        1.0.5. Any of the preceding compositions wherein the basic amino        acid is L-arginine.        1.0.6. Any of the preceding compositions wherein the basic amino        acid is partially or wholly in salt form.        1.0.7. Any of the preceding compositions wherein the salt of the        basic amino acid comprises arginine bicarbonate.        1.0.8. Any of the preceding compositions wherein the salt of the        basic amino acid is formed in situ in the formulation by        neutralization of the basic amino acid with an acid or a salt of        an acid.        1.0.9. Any of the preceding compositions wherein the salt of the        basic amino acid is formed by neutralization of the basic amino        acid to form a premix prior to combination with the fluoride        salt.        1.0.10. Any of the preceding compositions wherein the basic        amino acid is present in an amount corresponding to about 0.1 to        about 20%, e.g., about 1 wt. % to about 15 wt. %, of the total        composition weight, the weight of the basic amino acid being        calculated as free base form.        1.0.11. Composition 1.0.10 wherein the basic amino acid is        present in an amount of about 7.5 wt. % of the total composition        weight.        1.0.12. Composition 1.0.10 wherein the basic amino acid is        present in an amount of about 5 wt. % of the total composition        weight.        1.0.13. Composition 1.0.10 wherein the basic amino acid is        present in an amount of about 3.75 wt. % of the total        composition weight.        1.0.14. Composition 1.0.10 wherein the basic amino acid is        present in an amount of about 1.5 wt. % of the total composition        weight.        1.0.15. Any of the preceding compositions wherein the fluoride        salt is stannous fluoride, sodium fluoride, potassium fluoride,        sodium monofluorophosphate, sodium fluorosilicate, ammonium        fluorosilicate, amine fluoride (e.g.,        N′-octadecyltrimethylendiamine-N,N,N′-tris(2-ethanol)-dihydrofluoride),        ammonium fluoride, titanium fluoride, hexafluorosulfate, and        combinations thereof.        1.0.16. Any of the preceding compositions wherein the fluoride        salt is a fluorophosphate.        1.0.17. Any of the preceding composition wherein the fluoride        salt is sodium monofluorophosphate.        1.0.18. Any of the preceding compositions wherein the fluoride        salt is present in an amount of about 0.01 wt. % to about 2 wt.        % of the total composition weight.        1.0.19. Any of the preceding compositions wherein the soluble        fluoride salt provides fluoride ion in an amount of about 0.1 to        about 0.2 wt. % of the total composition weight.        1.0.20. Any of the preceding compositions wherein the soluble        fluoride salt provides fluoride ion in an amount of from about        50 to 25,000 ppm.        1.0.21. Any of the preceding compositions which is a mouthwash        having about 100 to about 250 ppm available fluoride ion.        1.0.22. Any of which is a dentifrice having about 750 to about        2000 ppm available fluoride ion.        1.0.23. Any of the preceding compositions wherein the        composition comprises about 750 to about 2000 ppm fluoride ion.        1.0.24. Any of the preceding compositions wherein the        composition comprises about 1000 to about 1500 ppm fluoride ion.        1.0.25. Any of the preceding compositions wherein the        composition comprises about 1450 ppm fluoride ion.        1.0.26. Any of the preceding compositions wherein the pH is        between about 6 and about 10.5.        1.0.27. Any of the preceding compositions wherein the pH is        between about 8.0 and about 10.5.        1.0.28. Any of the preceding compositions wherein the pH is        between about 8.0 and about 10.0.        1.0.29. Any of the preceding compositions wherein the pH is        about 8.0, about 9.0, or about 9.5.        1.0.30. Any of the preceding compositions wherein the        precipitated calcium carbonate has a D₅₀ of 3.5-7.0 microns, a        D₉₀ of 7.0-14.5 microns and a D₁₀ of 0.6-1.7 microns.        1.0.31. Any of the preceding compositions wherein the        precipitated calcium carbonate in an amount of about 30 wt. % to        about 50 wt. % of the total composition weight.        1.0.32. Any of the preceding compositions wherein the        precipitated calcium carbonate (PCC) has an average particle        size of D₅₀ of 3.5-7.0 microns, a D₉₀ of 7.0-14.5 microns and a        D₁₀ of 0.6-1.7 microns and water absorption of greater than 25        g/100 g.        1.0.33. Any of the preceding compositions comprising a small        particle abrasive fraction of at least about 5% having a d50 of        less than about 5 micrometers.        1.0.34. Any of the preceding compositions having an RDA of less        than about 150, e.g., about 40 to about 140.        1.0.35. Any of the preceding compositions comprising at least        one surfactant.        1.0.36. Any of the preceding compositions comprising at least        one surfactant selected from sodium lauryl sulfate,        cocamidopropyl betaine, and combinations thereof.        1.0.37. Any of the preceding compositions comprising an anionic        surfactant.        1.0.38. Any of the preceding compositions comprising sodium        lauryl sulfate.        1.0.39. Any of the preceding compositions comprising at least        one humectant in addition to glycerin.        1.0.40. Any of the preceding compositions comprising at least        one polymer.        1.0.41. Any of the preceding compositions comprising at least        one polymer selected from polyethylene glycols, polyvinylmethyl        ether maleic acid copolymers, polysaccharides (e.g., cellulose        derivatives, for example carboxymethyl cellulose, or        polysaccharide gums, for example xanthan gum or carrageenan        gum), and combinations thereof.        1.0.42. Any of the preceding compositions comprising gum strips        or fragments.        1.0.43. Any of the preceding compositions comprising flavoring,        fragrance and/or coloring.        1.0.44. Any of the preceding compositions comprising water.        1.0.45. Any of the preceding compositions comprising an        antibacterial agent.        1.0.46. Any of the preceding compositions comprising an        antibacterial agent selected from herbal extracts and essential        oils (e.g., rosemary extract, tea extract, magnolia extract,        thymol, menthol, eucalyptol, geraniol, carvacrol, citral,        hinokitol, catechol, methyl salicylate, epigallocatechin        gallate, epigallocatechin, gallic acid, miswak extract,        sea-buckthorn extract), bisguanide antiseptics (e.g.,        chlorhexidine, alexidine or octenidine), quaternary ammonium        compounds (e.g., cetylpyridinium chloride (CPC), benzalkonium        chloride, tetradecylpyridinium chloride (TPC),        N-tetradecyl-4-ethylpyridinium chloride (TDEPC)), phenolic        antiseptics, hexetidine, octenidine, sanguinarine, povidone        iodine, delmopinol, salifluor, metal ions (e.g., zinc salts, for        example, zinc citrate, stannous salts, copper salts, iron        salts), sanguinarine, propolis and oxygenating agents (e.g.,        hydrogen peroxide, buffered sodium peroxyborate or        peroxycarbonate), phthalic acid and its salts, monoperthalic        acid and its salts and esters, ascorbyl stearate, oleoyl        sarcosine, alkyl sulfate, dioctyl sulfosuccinate,        salicylanilide, domiphen bromide, delmopinol, octapinol and        other piperidino derivatives, nicin preparations, chlorite        salts; and mixtures of any of the foregoing.        1.0.47. Any of the preceding compositions comprising a whitening        agent.        1.0.48. Any of the preceding compositions comprising a whitening        agent selected from a whitening active selected from the group        consisting of peroxides, metal chlorites, perborates,        percarbonates, peroxyacids, hypochlorites, and combinations        thereof.        1.0.49. Any of the preceding compositions further comprising        hydrogen peroxide or a hydrogen peroxide source, e.g., urea        peroxide or a peroxide salt or complex (e.g., such as        peroxyphosphate, peroxycarbonate, perborate, peroxysilicate, or        persulphate salts; for example calcium peroxyphosphate, sodium        perborate, sodium carbonate peroxide, sodium peroxyphosphate,        and potassium persulfate), or hydrogen peroxide polymer        complexes such as hydrogen peroxide-polyvinyl pyrrolidone        polymer complexes.        1.0.50. Any of the preceding compositions comprising an        antioxidant, e.g., selected from the group consisting of        Co-enzyme Q10, PQQ, Vitamin D, Vitamin C, Vitamin E, Vitamin A,        anethole-dithiothione, and mixtures thereof.        1.0.51. Any of the preceding composition comprising a Zn²⁺ ion        source, e.g., zinc citrate.        1.0.52. Any of the preceding compositions comprising an        antibacterial agent in an amount of about 0.01 to about 5 wt. %        of the total composition weight.        1.0.53. Any of the preceding compositions further comprising an        agent that interferes with or prevents bacterial attachment,        e.g., solbrol or chitosan.        1.0.54. Any of the preceding compositions further comprising an        anti-calculus agent.        1.0.55. Any of the preceding compositions further comprising an        anti-calculus agent which is a polyphosphate, e.g.,        pyrophosphate, tripolyphosphate, or hexametaphosphate, e.g., in        sodium salt form.        1.0.56. Any of the preceding compositions further comprising a        source of calcium and phosphate selected from (i) calcium-glass        complexes, e.g., calcium sodium phosphosilicates, and (ii)        calcium-protein complexes, e.g., casein phosphopeptide-amorphous        calcium phosphate.        1.0.57. Any of the preceding compositions further comprising a        soluble calcium salt, e.g., selected from calcium sulfate,        calcium chloride, calcium nitrate, calcium acetate, calcium        lactate, and combinations thereof.        1.0.58. Any of the preceding compositions further comprising a        physiologically acceptable potassium salt, e.g., potassium        nitrate or potassium chloride, in an amount effective to reduce        dentinal sensitivity.        1.0.59. Any of the preceding compositions comprising from about        0.1% to about 7.5% of a physiologically acceptable potassium        salt, e.g., potassium nitrate and/or potassium chloride.        1.0.60. Any of the preceding compositions effective upon        application to the oral cavity, e.g., with brushing, to (i)        reduce or inhibit formation of dental caries, (ii) reduce,        repair or inhibit pre-carious lesions of the enamel, e.g., as        detected by quantitative light-induced fluorescence (QLF) or        electrical caries measurement (ECM), (iii) reduce or inhibit        demineralization and promote remineralization of the teeth, (iv)        reduce hypersensitivity of the teeth, (v) reduce or inhibit        gingivitis, (vi) promote healing of sores or cuts in the        mouth, (vii) reduce levels of acid producing bacteria, (viii) to        increase relative levels of arginolytic bacteria, (ix) inhibit        microbial biofilm formation in the oral cavity, (x) raise and/or        maintain plaque pH at levels of at least pH 5.5 following sugar        challenge, (xi) reduce plaque accumulation, (xii) treat, relieve        or reduce dry mouth, (xiii) clean the teeth and oral        cavity, (xiv) reduce erosion, (xv) whiten teeth, (xvi) immunize        the teeth against cariogenic bacteria and/or (xvii) promote        systemic health, including cardiovascular health, e.g., by        reducing potential for systemic infection via the oral tissues.        1.0.61. A composition obtained or obtainable by combining the        ingredients as set forth in any of the preceding compositions.        1.0.62. Any of the preceding compositions in a form selected        from mouthrinse, toothpaste, tooth gel, tooth powder,        non-abrasive gel, mousse, foam, mouth spray, lozenge, oral        tablet, dental implement, chewing gum and pet care product.        1.0.63. Any of the preceding compositions wherein the        composition is toothpaste.        1.0.64. Any of the preceding compositions wherein the        composition is a toothpaste optionally further comprising one or        more of one or more of water, abrasives, surfactants, foaming        agents, vitamins, polymers, enzymes, humectants, thickeners,        antimicrobial agents, preservatives, flavorings, colorings        and/or combinations thereof.        1.0.65. Any of the preceding compositions, wherein the amount of        glycerin if from 15%-17% by wt. (e.g., about 16% by wt.)        1.0.66. Any of the preceding compositions 1.0-1.0.64 wherein the        amount of glycerin is from 0.1 to 7% by wt. (e.g., about 6% by        wt.).        1.0.67. Any of the preceding compositions, wherein the amount of        water (e.g., free water) is from 30%-60% by wt.        1.0.68. Any of the preceding compositions, wherein the amount of        water (e.g., free water) is from 30%-35% by wt.        1.0.69. Any of the preceding compositions, wherein the amount of        water (e.g., free water) is from 40%-45% by wt.        1.0.70. Any of the preceding compositions 1.0-1.0.62 and        1.0.65-1.0.69 wherein the composition is a mouthwash.        1.0.71. Any of the preceding compositions, wherein the oral care        composition comprises:    -   a. purified water from 30-50% by wt.    -   b. precipitated calcium carbonate from 35-45% by wt. (e.g, 40%        by wt)    -   c. glycerin from 5-20% by wt. (e.g., 15% by wt)    -   d. sodium lauryl sulfate from 4%-7% by wt.    -   e. sodium monofluorophosphate from 0.50%-1.25% by wt. (e.g.,        1.1% by wt.)    -   f. sodium bicarbonate from 0.5%-1.50% by wt.    -   g. arginine from 1%-2% by wt. (e.g., 1.5% by wt)    -   h. polysaccharide gum from 0.1-0.4% by wt. (e.g. about 0.2% by        wt.)        1.0.72. Any of compositions 1.0-1.0.70, wherein the oral care        composition comprises:    -   a. purified water from 30-35% by wt. (e.g., about 33% by wt.)    -   b. precipitated calcium carbonate from 35-45% by wt. (e.g.,        about 40 wt %)    -   c. glycerin from 15-20% by wt (e.g., about 16 wt %).    -   d. sodium lauryl sulfate from 0.75%-1.75% by wt.    -   e. sodium monofluorophosphate from 0.75%-1.5% by wt. (1.1% by        wt.)    -   f. tetrasodium pyrophosphate from 0.15-0.60% by wt.    -   g. Arginine from 1%-2% by wt. (e.g., 1.5% by wt. arginine e.g.,        L-arginine);    -   h. xanthan gum 0.1-0.4% by wt. (e.g. about 0.2% by wt.)        1.0.73. Any of compositions 1.0-1.0.70, wherein the oral care        composition comprises:    -   a. purified water from 40-47% by wt. (e.g., about 43% by wt)        (e.g., about 46% by wt.)    -   b. precipitated calcium carbonate from 35-45% by wt. (e.g.,        about 39 wt %)    -   c. glycerin from 0.1-7% by wt (e.g., about 6 wt %).    -   d. sodium lauryl sulfate (e.g., 35% sodium lauryl sulfate) from        0.75%-2.0% by wt. (e.g., in granule form) or (e.g., about        4.5%-5.5%—liquid from) (e.g., about 5.0% liquid)    -   e. sodium monofluorophosphate from 0.75%-1.5% by wt.    -   f. tetrasodium pyrophosphate from 0.15-0.60% by wt. (e.g., 0.2%        by wt.)    -   g. arginine from 1%-2% by wt. (e.g., 1.5% by wt. arginine e.g.,        L-arginine).    -   h. sodium bicarbonate from 0.5-1.5% by wt. (e.g., 1.1% by wt.)    -   i. sodium carboxymethylcellulose and polyionic cellulose from        0.75%-1.25% by wt.        1.0.74. Any of the preceding compositions, wherein the        composition does not contain any sorbitol or is substantially        free of sorbitol.

In another embodiment, the invention encompasses a method (Method 2) forpreparing an oral composition, e.g., any Compositions under 1.0 et seq,supra, comprising

-   -   i. forming a premix by combining a basic amino acid in a gel        phase with an acid and/or salt thereof to obtain a pH of less        than about 10, and    -   ii. combining the premix with other ingredients of the        formulation, including a soluble fluoride salt.

Method 2 thus comprises, e.g., the following embodiments:

-   -   2.1. Any of the preceding methods wherein the fluoride salt is        selected from stannous fluoride, sodium fluoride, potassium        fluoride, sodium monofluorophosphate, sodium fluorosilicate,        ammonium fluorosilicate, amine fluoride, ammonium fluoride, and        combinations thereof    -   2.2. Any of the preceding methods wherein the fluoride salt is a        fluorophosphate.    -   2.3. Any of the preceding methods wherein the fluoride salt is        sodium monofluorophosphate.    -   2.4. Any of the preceding methods wherein the basic amino acid        is selected from arginine, lysine, citrullene, ornithine,        creatine, histidine, diaminobutanoic acid, diaminoproprionic        acid, salts and combinations thereof.    -   2.5. Any of the preceding methods wherein the basic amino acid        has the L-configuration.    -   2.6. Any of the preceding methods wherein the basic amino acid        is arginine.    -   2.7. Any of the preceding methods when carried out at room        temperature and pressure.    -   2.8. Any of the preceding methods wherein the ingredients and        their respective amounts are as set forth in any of the        embodiments as set forth under Compositions 1.0 et seq.

In another embodiment, the invention encompasses a method (Method 3) toimprove oral health comprising applying an effective amount of the oralcomposition of any of the embodiments under Compositions 1.0, et seq. tothe oral cavity of a subject in need thereof, e.g., a method to

-   -   i. reduce or inhibit formation of dental caries,    -   ii. reduce, repair or inhibit early enamel lesions, e.g., as        detected by quantitative light-induced fluorescence (QLF) or        electrical caries measurement (ECM),    -   iii. reduce or inhibit demineralization and promote        remineralization of the teeth,    -   iv. reduce hypersensitivity of the teeth,    -   v. reduce or inhibit gingivitis,    -   vi. promote healing of sores or cuts in the mouth,    -   vii. reduce levels of acid producing bacteria,    -   viii. to increase relative levels of arginolytic bacteria,    -   ix. inhibit microbial biofilm formation in the oral cavity,    -   x. raise and/or maintain plaque pH at levels of at least pH 5.5        following sugar challenge,    -   xi. reduce plaque accumulation,    -   xii. treat, relieve or reduce dry mouth,    -   xiii. clean the teeth and oral cavity,    -   xiv. reduce erosion,    -   xv. whiten teeth,    -   xvi. immunize the teeth against cariogenic bacteria; and/or    -   xvii. promote systemic health, including cardiovascular health,        e.g., by reducing potential for systemic infection via the oral        tissues.

The invention further comprises the use of arginine in the manufactureof a Composition of the Invention, e.g., for use in any of theindications set forth in Method 3.

The invention further provides an oral care composition of any ofCompositions 1.0, et seq, for use in the treatment of at least one ofdemineralized teeth and enamel lesions within an oral cavity of asubject, or for enhancing the mineralization of teeth within an oralcavity of a subject.

The invention further provides the use of an oral care composition ofany of Compositions 1.0 et seq for the manufacture of a medicament forenhancing the mineralization of teeth within an oral cavity of asubject.

The invention further provides a method of mineralizing at least one ofdemineralized teeth and enamel lesions within an oral cavity of asubject, the method comprising treating the oral cavity with an oralcare composition of any of Compositions 1.0 et seq.

It may therefore be seen by the skilled practitioner in the oral careart that a number of different yet surprising technical effects andadvantages can result from the formulation, and use, of an oral carecomposition, for example a dentifrice, in accordance with one or moreaspects of the invention, which are directed to the provision ofdifferent combinations of active components or ingredients, andpreferably their respective amounts, within the composition.

Levels of active ingredients will vary based on the nature of thedelivery system and the particular active. For example, the basic aminoacid may be present at levels from, e.g., about 0.1 to about 20 wt %(expressed as weight of free base), e.g., about 0.1 to about 3 wt % fora mouthrinse, about 1 to about 10 wt % for a consumer toothpaste orabout 7 to about 20 wt % for a professional or prescription treatmentproduct. Fluoride may be present at levels of, e.g., about 25 to about25,000 ppm, for example about 25 to about 250 ppm for a mouthrinse,about 750 to about 2,000 ppm for a consumer toothpaste, or about 2,000to about 25,000 ppm for a professional or prescription treatmentproduct. Levels of antibacterial will vary similarly, with levels usedin toothpaste being e.g., about 5 to about 15 times greater than used inmouthrinse.

Measurements

RDA: RDA is an abbreviation for radioactive dentin abrasion, a relativemeasure of abrasivity. Typically, extracted human or cow teeth areirradiated in a neutron flux, mounted in methylmethacrylate (bone glue),stripped of enamel, inserted into a brushing-machine, brushed byAmerican Dental Association (ADA) standards (reference toothbrush, 150 gpressure, 1500 strokes, 4-to-1 water-toothpaste slurry). Theradioactivity of the rinse water is then measured and recorded. Forexperimental control, the test is repeated with an ADA referencetoothpaste made of calcium pyrophosphate, with this measurement given avalue of 100 to calibrate the relative scale. See, e.g., Hefferren,Journal of Dental Research, 55:4, 1976, 563-573, and U.S. Pat. Nos.4,340,583; 4,420,312; and 4,421,527.

PCR or pellicle cleaning ratio is a measure of the effectiveness of thedentifrice to remove stains, e.g. described U.S. Pat. Nos. 5,658,553 and5,651,958. Typically, a clear pellicle material is applied to a bovinetooth which is then stained with a combination of the pellicle materialand tea, coffee, and FeCl₃, which is subsequently treated with thecomposition, and the change in the reflectance of the tooth surfacebefore and after treatment is the PCR value.

Basic Amino Acids

The basic amino acids which can be used in the compositions and methodsof the invention include not only naturally occurring basic amino acids,such as arginine, lysine, and histidine, but also any basic amino acidshaving a carboxyl group and an amino group in the molecule, which arewater-soluble and provide an aqueous solution with a pH of 7 or greater.

Accordingly, basic amino acids include, but are not limited to,arginine, lysine, citrullene, ornithine, creatine, histidine,diaminobutanoic acid, diaminoproprionic acid, salts thereof orcombinations thereof. In a particular embodiment, the basic amino acidsare selected from arginine, citrullene, and ornithine.

In certain embodiments, the basic amino acid is arginine, for example,1-arginine, or a salt thereof.

In some embodiments the basic amino acid comprises at least oneintermediate produced in the arginine deiminase system. Theintermediates produced in the arginine deiminase system may be useful inan oral care composition to provide plaque neutralization for cariescontrol and/or prevention. Arginine is a natural basic amino acid thatmay be found in the oral cavity. Arginine in the mouth may be utilizedby certain dental plaque bacterial strains such as S. sanguis, S.gordonii, S. parasanguis, S. rattus, S. milleri, S. anginosus, S.faecalis, A. naeslundii, A. odonolyticus, L. cellobiosus, L. brevis, L.fermentum, P. gingivalis, and T. denticola for their survival. Suchorganisms may perish in an acidic environment that may be present atareas close to the tooth surface where acidogenic and aciduriccariogenic strains may use sugars to produce organic acids. Thus, thesearginolytic strains may break down arginine to ammonia to providealkalinity to survive and, in addition, buffer the plaque and make ahostile environment for the cariogenic systems.

Such arginolytic organisms may catabolize arginine by an internalcellular enzyme pathway system called the “arginine deiminase system”whereby intermediates in the pathway are formed. In this pathway,L-arginine may be broken down to L-citrulline and ammonia by argininedeiminase. L-citrulline may then be broken down by ornithanetrancarbamylase in the presence of inorganic phosphate to L-ornithineand carbamyl phosphate. Carbamate kinase may then break down carbamylphosphate to form another molecule of ammonia and carbon dioxide, and inthe process also forms ATP (adenosine 5′-triphosphate). ATP may be usedby the arginolytic bacteria as an energy source for growth. Accordingly,when utilized, the arginine deiminase system may yield two molecules ofammonia.

It has been found that, in some embodiments, the ammonia may help inneutralizing oral plaque pH to control and/or prevent dental caries.

The oral care composition of some embodiments of the present inventionmay include intermediates produced in the arginine deiminase system.Such intermediates may include citrulline, ornithine, and carbamylphosphate. In some embodiments, the other care composition includescitrulline. In some embodiments, the oral care composition includesornithine. In some embodiments, the oral care composition includescarbamyl phosphate. In other embodiments, the oral care compositionincludes any combination of citrulline, ornithine, carbamyl phosphate,and/or other intermediates produced by the arginine deiminase system.

The oral care composition may include the above described intermediatesin an effective amount. In some embodiments, the oral care compositionincludes about 1 mmol/L to about 10 mmol/L intermediate. In otherembodiments, the oral care composition includes about 3 mmol/L to about7 mmol/L intermediate. In other embodiments, the oral care compositionincludes about 5 mmol/L intermediate.

The compositions of the invention are intended for topical use in themouth and so salts for use in the present invention should be safe forsuch use, in the amounts and concentrations provided. Suitable saltsinclude salts known in the art to be pharmaceutically acceptable saltsare generally considered to be physiologically acceptable in the amountsand concentrations provided. Physiologically acceptable salts includethose derived from pharmaceutically acceptable inorganic or organicacids or bases, for example acid addition salts formed by acids whichform a physiological acceptable anion, e.g., hydrochloride or bromidesalt, and base addition salts formed by bases which form aphysiologically acceptable cation, for example those derived from alkalimetals such as potassium and sodium or alkaline earth metals such ascalcium and magnesium. Physiologically acceptable salts may be obtainedusing standard procedures known in the art, for example, by reacting asufficiently basic compound such as an amine with a suitable acidaffording a physiologically acceptable anion.

In various embodiments, the basic amino acid is present in an amount ofabout 0.5 wt. % to about 20 wt. % of the total composition weight, about1 wt. % to about 15 wt. % of the total composition weight, for exampleabout 1.5 wt. %, about 3.75 wt. %, about 5 wt. %, or about 7.5 wt. %, orabout 10 wt % of the total composition weight.

Fluoride Ion Source

The oral care compositions may further include one or more fluoride ionsources, e.g., soluble fluoride salts. A wide variety of fluorideion-yielding materials can be employed as sources of soluble fluoride inthe present compositions. Examples of suitable fluoride ion-yieldingmaterials are found in U.S. Pat. No. 3,535,421, to Briner et al.; U.S.Pat. No. 4,885,155, to Parran, Jr. et al. and U.S. Pat. No. 3,678,154,to Widder et al., incorporated herein by reference.

Representative fluoride ion sources include, but are not limited to,stannous fluoride, sodium fluoride, potassium fluoride, sodiummonofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate,amine fluoride, ammonium fluoride, and combinations thereof. In certainembodiments the fluoride ion source includes stannous fluoride, sodiumfluoride, sodium monofluorophosphate as well as mixtures thereof.

In certain embodiments, the oral care composition of the invention mayalso contain a source of fluoride ions or fluorine-providing ingredientin amounts sufficient to supply about 25 ppm to 25,000 ppm of fluorideions, generally at least about 500 ppm, e.g., about 500 to about 2000ppm, e.g., about 1000 to about 1600 ppm, e.g., about 1450 ppm. Theappropriate level of fluoride will depend on the particular application.A mouthwash, for example, would typically have about 100 to about 250ppm fluoride. A toothpaste for general consumer use would typically haveabout 1000 to about 1500 ppm, with pediatric toothpaste having somewhatless. A dentifrice or coating for professional application could have asmuch as 5,000 or even 25,000 ppm fluoride.

Fluoride ion sources may be added to the compositions of the inventionat a level of about 0.01 wt. % to about 10 wt. % in one embodiment orabout 0.03 wt. % to about 5 wt. %, and in another embodiment about 0.1wt. % to about 1 wt. % by weight of the composition in anotherembodiment. Weights of fluoride salts to provide the appropriate levelof fluoride ion will obviously vary based on the weight of the counterion in the salt.

Particulates and Abrasives

The Compositions of the Invention comprise precipitated calciumcarbonate. In addition to precipitated calcium carbonate, thecompositions of the invention may comprise a calcium phosphate abrasive,e.g., tricalcium phosphate (Ca₃(PO₄)₂), hydroxyapatite(Ca₁₀(PO₄)₆(OH)₂), or dicalcium phosphate dihydrate (CaHPO₄.2H₂O, alsosometimes referred to herein as DiCal) or calcium pyrophosphate.Alternatively, in addition to precipitated calcium carbonate, thecompositions may also comprise natural calcium carbonate.

In addition to precipitated calcium carbonate, the compositions mayinclude one or more additional particulate materials, for example silicaabrasives such as precipitated silicas having a mean particle size of upto about 20 microns, such as Zeodent 115®, marketed by J. M. Huber.Other useful abrasives also include sodium metaphosphate, potassiummetaphosphate, aluminum silicate, calcined alumina, bentonite or othersiliceous materials, or combinations thereof.

The silica abrasive polishing materials useful herein, as well as theother abrasives, generally have an average particle size ranging betweenabout 0.1 and about 30 microns, about between 5 and about 15 microns.The silica abrasives can be from precipitated silica or silica gels,such as the silica xerogels described in U.S. Pat. No. 3,538,230, toPader et al. and U.S. Pat. No. 3,862,307, to Digiulio, both incorporatedherein by reference. Particular silica xerogels are marketed under thetrade name Syloid® by the W. R. Grace & Co., Davison Chemical Division.The precipitated silica materials include those marketed by the J. M.Huber Corp. under the trade name Zeodent®, including the silica carryingthe designation Zeodent 115 and 119. These silica abrasives aredescribed in U.S. Pat. No. 4,340,583, to Wason, incorporated herein byreference.

In certain embodiments, in addition to precipitated calcium carbonate,the abrasive materials useful in the practice of the oral carecompositions in accordance with the invention include silica gels andprecipitated amorphous silica having an oil absorption value of aboutless than 100 cc/100 g silica and in the range of about 45 cc/100 g toabout 70 cc/100 g silica. Oil absorption values are measured using theASTA Rub-Out Method D281. In certain embodiments, the silicas arecolloidal particles having an average particle size of about 3 micronsto about 12 microns, and about 5 to about 10 microns.

In particular embodiments, the particulate or abrasive materialscomprise a large fraction of very small particles, e.g., having a d50less than about 5 microns, for example small particle silica (SPS)having a d50 of about 3 to about 4 microns, for example Sorbosil AC43®(Ineos). Such small particles are particularly useful in formulationstargeted at reducing hypersensitivity. The small particle component maybe present in combination with a second larger particle abrasive. Incertain embodiments, for example, the formulation comprises about 3 toabout 8% SPS and about 25 to about 45% of a conventional abrasive.

Low oil absorption silica abrasives particularly useful in the practiceof the invention are marketed under the trade designation Sylodent XWA®by Davison Chemical Division of W.R. Grace & Co., Baltimore, Md. 21203.Sylodent 650 XWA®, a silica hydrogel composed of particles of colloidalsilica having a water content of about 29% by weight averaging about 7to about 10 microns in diameter, and an oil absorption of less thanabout 70 cc/100 g of silica is an example of a low oil absorption silicaabrasive useful in the practice of the present invention. The abrasiveis present in the oral care composition of the present invention at aconcentration of about 10 to about 60% by weight, in other embodimentabout 20 to about 45% by weight, and in another embodiment about 30 toabout 50% by weight.

Precipitated calcium carbonate is generally made by calcining limestone,to make calcium oxide (lime), which can then be converted back tocalcium carbonate by reaction with carbon dioxide in water. Precipitatedcalcium carbonate has a different crystal structure from natural calciumcarbonate. It is generally more friable and more porous, thus havinglower abrasivity and higher water absorption. For use in the presentinvention, the particles are small, e.g., having an average particlesize of 1-5 microns, and e.g., no more than 0.1%, preferably no morethan 0.05% by weight of particles which would not pass through a 325mesh. The particles may for example have a D₉₀ of 7.0-14.5 microns; aD₅₀ of 3.5-7 microns, and a D₁₀ of 0.6-1.7 microns, e.g., 1.2-1.4, e.g.about 1.3 microns. The particles have relatively high-water absorption,e.g., at least 25 g/100 g, e.g. 30-70 g/100 g. Examples of commerciallyavailable products suitable for use in the present invention include,for example, Carbolag® 15 Plus from Lagos Industria Quimica.

In some embodiments, in addition to precipitated calcium carbonate,there may also be natural calcium carbonate. Natural calcium carbonateis found in rocks such as chalk, limestone, marble and travertine. It isalso the principle component of egg shells and the shells of mollusks.The natural calcium carbonate abrasive of the invention is typically afinely ground limestone which may optionally be refined or partiallyrefined to remove impurities. For use in the present invention, thematerial has an average particle size of less than 10 microns, e.g., 3-7microns, e.g. about 5.5 microns. Because natural calcium carbonate maycontain a high proportion of relatively large particles of not carefullycontrolled, which may unacceptably increase the abrasivity, preferablyno more than 0.01%, preferably no more than 0.004% by weight ofparticles would not pass through a 325 mesh. The material has strongcrystal structure, and is thus much harder and more abrasive thanprecipitated calcium carbonate. The tap density for the natural calciumcarbonate is for example between 1 and 1.5 g/cc, e.g., about 1.2 forexample about 1.19 g/cc. There are different polymorphs of naturalcalcium carbonate, e.g., calcite, aragonite and vaterite, calcite beingpreferred for purposes of this invention. An example of a commerciallyavailable product suitable for use in the present invention includesVicron® 25-11 FG from GMZ.

Foaming Agents

The oral care compositions of the invention also may include an agent toincrease the amount of foam that is produced when the oral cavity isbrushed.

Illustrative examples of agents that increase the amount of foaminclude, but are not limited to polyoxyethylene and certain polymersincluding, but not limited to, alginate polymers.

The polyoxyethylene may increase the amount of foam and the thickness ofthe foam generated by the oral care carrier component of the presentinvention. Polyoxyethylene is also commonly known as polyethylene glycol(“PEG”) or polyethylene oxide. The polyoxyethylenes suitable for thisinvention will have a molecular weight of about 200,000 to about7,000,000. In one embodiment the molecular weight will be about 600,000to about 2,000,000 and in another embodiment about 800,000 to about1,000,000. Polyox® is the trade name for the high molecular weightpolyoxyethylene produced by Union Carbide.

The polyoxyethylene may be present in an amount of about 1% to about90%, in one embodiment about 5% to about 50% and in another embodimentabout 10% to about 20% by weight of the oral care carrier component ofthe oral care compositions of the present invention. The dosage offoaming agent in the oral care composition (i.e., a single dose) isabout 0.01 to about 0.9% by weight, about 0.05 to about 0.5% by weight,and in another embodiment about 0.1 to about 0.2% by weight.

Surfactants

Another agent optionally included in the oral care composition of theinvention is a surfactant or a mixture of compatible surfactants.Suitable surfactants are those which are reasonably stable throughout awide pH range, for example, anionic, cationic, nonionic or zwitterionicsurfactants.

Suitable surfactants are described more fully, for example, in U.S. Pat.No. 3,959,458, to Agricola et al.; U.S. Pat. No. 3,937,807, to Haefele;and U.S. Pat. No. 4,051,234, to Gieske et al., which are incorporatedherein by reference.

In certain embodiments, the anionic surfactants useful herein includethe water-soluble salts of alkyl sulfates having about 10 to about 18carbon atoms in the alkyl radical and the water-soluble salts ofsulfonated monoglycerides of fatty acids having about 10 to about 18carbon atoms. Sodium lauryl sulfate, sodium lauroyl sarcosinate andsodium coconut monoglyceride sulfonates are examples of anionicsurfactants of this type. Mixtures of anionic surfactants may also beutilized.

In another embodiment, cationic surfactants useful in the presentinvention can be broadly defined as derivatives of aliphatic quaternaryammonium compounds having one long alkyl chain containing about 8 toabout 18 carbon atoms such as lauryl trimethylammonium chloride, cetylpyridinium chloride, cetyl trimethylammonium bromide,di-isobutylphenoxyethyldimethylbenzylammonium chloride, coconutalkyltrimethylammonium nitrite, cetyl pyridinium fluoride, and mixturesthereof.

Illustrative cationic surfactants are the quaternary ammonium fluoridesdescribed in U.S. Pat. No. 3,535,421, to Briner et al., hereinincorporated by reference. Certain cationic surfactants can also act asgermicides in the compositions.

Illustrative nonionic surfactants that can be used in the compositionsof the invention can be broadly defined as compounds produced by thecondensation of alkylene oxide groups (hydrophilic in nature) with anorganic hydrophobic compound which may be aliphatic or alkylaromatic innature. Examples of suitable nonionic surfactants include, but are notlimited to, the Pluronics, polyethylene oxide condensates of alkylphenols, products derived from the condensation of ethylene oxide withthe reaction product of propylene oxide and ethylene diamine, ethyleneoxide condensates of aliphatic alcohols, long chain tertiary amineoxides, long chain tertiary phosphine oxides, long chain dialkylsulfoxides and mixtures of such materials.

In certain embodiments, zwitterionic synthetic surfactants useful in thepresent invention can be broadly described as derivatives of aliphaticquaternary ammonium, phosphomium, and sulfonium compounds, in which thealiphatic radicals can be straight chain or branched, and wherein one ofthe aliphatic substituents contains about 8 to about 18 carbon atoms andone contains an anionic water-solubilizing group, e.g., carboxy,sulfonate, sulfate, phosphate or phosphonate. Illustrative examples ofthe surfactants suited for inclusion into the composition include, butare not limited to, sodium alkyl sulfate, sodium lauroyl sarcosinate,cocoamidopropyl betaine and polysorbate 20, and combinations thereof.

In a particular embodiment, the Composition of the Invention comprisesan anionic surfactant, e.g., sodium lauryl sulfate.

The surfactant or mixtures of compatible surfactants can be present inthe compositions of the present invention in about 0.1% to about 5.0%,in another embodiment about 0.3% to about 3.0% and in another embodimentabout 0.5% to about 2.0% by weight of the total composition.

Flavoring Agents

The oral care compositions of the invention may also include a flavoringagent. Flavoring agents which are used in the practice of the presentinvention include, but are not limited to, essential oils as well asvarious flavoring aldehydes, esters, alcohols, and similar materials.Examples of the essential oils include oils of spearmint, peppermint,wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon,lemon, lime, grapefruit, and orange. Also useful are such chemicals asmenthol, carvone, and anethole. Certain embodiments employ the oils ofpeppermint and spearmint.

The flavoring agent is incorporated in the oral composition at aconcentration of about 0.1 to about 5% by weight and about 0.5 to about1.5% by weight. The dosage of flavoring agent in the individual oralcare composition dosage (i.e., a single dose) is about 0.001 to about0.05% by weight and in another embodiment about 0.005 to about 0.015% byweight.

Chelating Agents

The oral care compositions of the invention also may optionally includeone or more chelating agents able to complex calcium found in the cellwalls of the bacteria. Binding of this calcium weakens the bacterialcell wall and augments bacterial lysis.

Another group of agents suitable for use as chelating agents in thepresent invention are the soluble pyrophosphates. The pyrophosphatesalts used in the present compositions can be any of the alkali metalpyrophosphate salts. In certain embodiments, salts include tetra alkalimetal pyrophosphate, dialkali metal diacid pyrophosphate, trialkalimetal monoacid pyrophosphate and mixtures thereof, wherein the alkalimetals are sodium or potassium. The salts are useful in both theirhydrated and unhydrated forms. An effective amount of pyrophosphate saltuseful in the present composition is generally enough to provide atleast about 1.0 wt. % pyrophosphate ions, about 1.5 wt. % to about 6 wt.%, about 3.5 wt. % to about 6 wt. % of such ions.

Polymers

The oral care compositions of the invention also optionally include oneor more polymers, such as polyethylene glycols, polyvinylmethyl ethermaleic acid copolymers, polysaccharides (e.g., cellulose derivatives,for example carboxymethyl cellulose, or polysaccharide gums, for examplexanthan gum or carrageenan gum). Acidic polymers, for examplepolyacrylate gels, may be provided in the form of their free acids orpartially or fully neutralized water soluble alkali metal (e.g.,potassium and sodium) or ammonium salts. Certain embodiments includeabout 1:4 to about 4:1 copolymers of maleic anhydride or acid withanother polymerizable ethylenically unsaturated monomer, for example,methyl vinyl ether (methoxyethylene) having a molecular weight (M.W.) ofabout 30,000 to about 1,000,000. These copolymers are available forexample as Gantrez AN 139 (M.W. 500,000), AN 119 (M.W. 250,000) and S-97Pharmaceutical Grade (M.W. 70,000), of GAF Chemicals Corporation.

Other operative polymers include those such as the 1:1 copolymers ofmaleic anhydride with ethyl acrylate, hydroxyethyl methacrylate,N-vinyl-2-pyrollidone, or ethylene, the latter being available forexample as Monsanto EMA No. 1103, M.W. 10,000 and EMA Grade 61, and 1:1copolymers of acrylic acid with methyl or hydroxyethyl methacrylate,methyl or ethyl acrylate, isobutyl vinyl ether or N-vinyl-2-pyrrolidone.

Suitable generally, are polymerized olefinically or ethylenicallyunsaturated carboxylic acids containing an activated carbon-to-carbonolefinic double bond and at least one carboxyl group, that is, an acidcontaining an olefinic double bond which readily functions inpolymerization because of its presence in the monomer molecule either inthe alpha-beta position with respect to a carboxyl group or as part of aterminal methylene grouping. Illustrative of such acids are acrylic,methacrylic, ethacrylic, alpha-chloroacrylic, crotonic, beta-acryloxypropionic, sorbic, alpha-chlorsorbic, cinnamic, beta-styrylacrylic,muconic, itaconic, citraconic, mesaconic, glutaconic, aconitic,alpha-phenylacrylic, 2-benzyl acrylic, 2-cyclohexylacrylic, angelic,umbellic, fumaric, maleic acids and anhydrides. Other different olefinicmonomers copolymerizable with such carboxylic monomers includevinylacetate, vinyl chloride, dimethyl maleate and the like. Copolymerscontain sufficient carboxylic salt groups for water-solubility.

A further class of polymeric agents includes a composition containinghomopolymers of substituted acrylamides and/or homopolymers ofunsaturated sulfonic acids and salts thereof, in particular wherepolymers are based on unsaturated sulfonic acids selected fromacrylamidoalykane sulfonic acids such as 2-acrylamide 2 methylpropanesulfonic acid having a molecular weight of about 1,000 to about2,000,000, described in U.S. Pat. No. 4,842,847, Jun. 27, 1989 to Zahid,incorporated herein by reference.

Another useful class of polymeric agents includes polyamino acids,particularly those containing proportions of anionic surface-activeamino acids such as aspartic acid, glutamic acid and phosphoserine, asdisclosed in U.S. Pat. No. 4,866,161 Sikes et al., incorporated hereinby reference.

In preparing oral care compositions, it is sometimes necessary to addsome thickening material to provide a desirable consistency or tostabilize or enhance the performance of the formulation. In certainembodiments, the thickening agents are carboxyvinyl polymers,carrageenan, hydroxyethyl cellulose and water soluble salts of celluloseethers such as sodium carboxymethyl cellulose and sodium carboxymethylhydroxyethyl cellulose. Natural gums such as karaya, gum arabic, and gumtragacanth can also be incorporated. Colloidal magnesium aluminumsilicate or finely divided silica can be used as component of thethickening composition to further improve the composition's texture. Incertain embodiments, thickening agents in an amount of about 0.5% toabout 5.0% by weight of the total composition are used.

Enzymes

The oral care compositions of the invention may also optionally includeone or more enzymes. Useful enzymes include any of the availableproteases, glucanohydrolases, endoglycosidases, amylases, mutanases,lipases and mucinases or compatible mixtures thereof. In certainembodiments, the enzyme is a protease, dextranase, endoglycosidase andmutanase. In another embodiment, the enzyme is papain, endoglycosidaseor a mixture of dextranase and mutanase. Additional enzymes suitable foruse in the present invention are disclosed in U.S. Pat. No. 5,000,939 toDring et al., U.S. Pat. Nos. 4,992,420; 4,355,022; 4,154,815; 4,058,595;3,991,177; and 3,696,191 all incorporated herein by reference. An enzymeof a mixture of several compatible enzymes in the current inventionconstitutes about 0.002% to about 2% in one embodiment or about 0.05% toabout 1.5% in another embodiment or in yet another embodiment about 0.1%to about 0.5%.

Water

Water may also be present in the oral compositions of the invention.Water, employed in the preparation of commercial oral compositionsshould be deionized and free of organic impurities. Water commonly makesup the balance of the compositions and includes at least 30% by weightto about 60%. This amount of water includes the free water which isadded plus that amount which is introduced with other materials, such aswith sorbitol, or any components of the invention.

Humectants

Within certain embodiments of the oral compositions, it is alsodesirable to incorporate a humectant, in addition to the glycerinalready present, to prevent the composition from hardening upon exposureto air. Certain humectants can also impart desirable sweetness or flavorto dentifrice compositions. The humectant, on a pure humectant basis,generally includes about 5% to about 20% in one embodiment or about 6%,or about 16% in other embodiments by weight of the dentifricecomposition.

In addition to the already present glycerin, suitable humectants includeedible polyhydric alcohols such as sorbitol, xylitol, propylene glycolas well as other polyols and mixtures of these humectants. Mixtures ofglycerin and sorbitol may be used in certain embodiments as thehumectant component of the toothpaste compositions herein.

In addition to the above described components, the embodiments of thisinvention can contain a variety of optional dentifrice ingredients someof which are described below. Optional ingredients include, for example,but are not limited to, adhesives, sudsing agents, flavoring agents,sweetening agents, additional antiplaque agents, abrasives, and coloringagents. These and other optional components are further described inU.S. Pat. No. 5,004,597, to Majeti; U.S. Pat. No. 3,959,458 to Agricolaet al. and U.S. Pat. No. 3,937,807, to Haefele, all being incorporatedherein by reference.

Methods of Manufacture

The compositions of the present invention can be made using methodswhich are common in the oral product area.

In one illustrative embodiment, the oral care composition is made byMethod 2, described above, e.g., neutralizing arginine in a gel phasewith an acid selected from: lactic acid, glycolic acid, citric acid, andacetic acid, and mixing to form Premix 1.

Actives such as, for example, vitamins, CPC, fluoride, abrasives, andany other desired active ingredients are added to Premix 1 and mixed toform Premix 2.

A toothpaste base, for example, dicalcium phosphate is added to Premix 2and mixed. The final slurry is formed into an oral care product.

Composition Use

The present invention in its method aspect involves applying to the oralcavity a safe and effective amount of the compositions described herein.

The compositions and methods according to the invention are useful to amethod to protect the teeth by facilitating repair and remineralization,in particular to reduce or inhibit formation of dental caries, reduce orinhibit demineralization and promote remineralization of the teeth,reduce hypersensitivity of the teeth, and reduce, repair or inhibitearly enamel lesions, e.g., as detected by quantitative light-inducedfluorescence (QLF) or electronic caries monitor (ECM).

Quantitative Light-induced Fluorescence is a visible light fluorescencethat can detect early lesions and longitudinally monitor the progressionor regression. Normal teeth fluoresce in visible light; demineralizedteeth do not or do so only to a lesser degree. The area ofdemineralization can be quantified and its progress monitored. Bluelaser light is used to make the teeth auto fluoresce. Areas that havelost mineral have lower fluorescence and appear darker in comparison toa sound tooth surface. Software is used to quantify the fluorescencefrom a white spot or the area/volume associated with the lesion.Generally, subjects with existing white spot lesions are recruited aspanelists. The measurements are performed in vivo with real teeth. Thelesion area/volume is measured at the beginning of the clinical. Thereduction (improvement) in lesion area/volume is measured at the end of6 months of product use. The data is often reported as a percentimprovement versus baseline.

Electrical Caries Monitoring is a technique used to measure mineralcontent of the tooth based on electrical resistance. Electricalconductance measurement exploits the fact that the fluid-filled tubulesexposed upon demineralization and erosion of the enamel conductelectricity. As a tooth loses mineral, it becomes less resistive toelectrical current due to increased porosity. An increase in theconductance of the patient's teeth therefore may indicatedemineralization. Generally, studies are conducted of root surfaces withan existing lesion. The measurements are performed in vivo with realteeth. Changes in electrical resistance before and after 6 monthtreatments are made. In addition, a classical caries score for rootsurfaces is made using a tactile probe. The hardness is classified on athree point scale: hard, leathery, or soft. In this type of study,typically the results are reported as electrical resistance (highernumber is better) for the ECM measurements and an improvement inhardness of the lesion based on the tactile probe score.

The Compositions of the Invention are thus useful in a method to reduceearly enamel lesions (as measured by QLF or ECM) relative to acomposition lacking effective amounts of fluorine and/or arginine.

The Compositions of the invention are additionally useful in methods toreduce harmful bacteria in the oral cavity, for example methods toreduce or inhibit gingivitis, reduce levels of acid producing bacteria,to increase relative levels of arginolytic bacteria, inhibit microbialbiofilm formation in the oral cavity, raise and/or maintain plaque pH atlevels of at least about pH 5.5 following sugar challenge, reduce plaqueaccumulation, treat dry mouth, and/or clean the teeth and oral cavity.

Finally, by increasing the pH in the mouth and discouraging pathogenicbacteria, the Compositions of the Invention are useful to promotehealing of sores or cuts in the mouth.

The compositions and methods according to the invention can beincorporated into oral compositions for the care of the mouth and teethsuch as toothpastes, transparent pastes, gels, mouth rinses, sprays andchewing gum.

Enhancing oral health also provides benefits in systemic health, as theoral tissues can be gateways for systemic infections. Good oral healthis associated with systemic health, including cardiovascular health. Thecompositions and methods of the invention provide particular benefitsbecause basic amino acids, especially arginine, are sources of nitrogenwhich supply NO synthesis pathways and thus enhance microcirculation inthe oral tissues. Providing a less acidic oral environment is alsohelpful in reducing gastric distress and creates an environment lessfavorable to Heliobacter, which is associated with gastric ulcers.Arginine in particular is required for high expression of specificimmune cell receptors, for example T-cell receptors, so that argininecan enhance an effective immune response. The compositions and methodsof the invention are thus useful to enhance systemic health, includingcardiovascular health.

As used throughout, ranges are used as shorthand for describing each andevery value that is within the range. Any value within the range can beselected as the terminus of the range. In addition, all references citedherein are hereby incorporated by reference in their entireties. In theevent of a conflict in a definition in the present disclosure and thatof a cited reference, the present disclosure controls. It is understoodthat when formulations are described, they may be described in terms oftheir ingredients, as is common in the art, notwithstanding that theseingredients may react with one another in the actual formulation as itis made, stored and used, and such products are intended to be coveredby the formulations described.

The following examples further describe and demonstrate illustrativeembodiments within the scope of the present invention. The examples aregiven solely for illustration and are not to be construed as limitationsof this invention as many variations are possible without departing fromthe spirit and scope thereof. Various modifications of the invention inaddition to those shown and described herein should be apparent to thoseskilled in the art and are intended to fall within the appended claims.

EXAMPLES Example 1: Formulation

An optimized arginine toothpaste formulations are prepared using thefollowing ingredients:

TABLE A Weight % Composition Composition Composition Material A B CPurified Water q.s. q.s. q.s. Flavor and Sweetener 1.175 1.175 1.175Precipitated Calcium 40 39 39 Carbonate Glycerin 15.0 6.0 6.0 AnionicSurfactant (e.g., 5.0 5.0 — 35% Sodium Lauryl Sulfate - Liquid) Sodium1.1 1.1 1.1 monofluorophosphate Tetrasodium 0.2 0.2 0.2 pyrophosphateSodium Carboxymethyl 0.85 1.0 1.0 Celluose Sodium Bicarbonate 1.1 1.11.1 Polysaccharide gum — 0.2 0.2 Benzyl Alcohol 0.3 0.4 0.4 L-Arginine1.5 1.5 1.5 95% NA Lauryl Sulfate — — 1.85 Granules USP, EP Total 100100 100

The invention claimed is:
 1. An oral care composition comprising i. aneffective amount of arginine in free or salt form; ii. an effectiveamount of sodium monofluorophosphate; iii. an effective amount ofprecipitated calcium carbonate (PCC); iv. an effective amount ofglycerin, wherein the amount of glycerin is from 0.1 to 7% by wt.wherein the composition comprises purified water in an amount from40%-45% by wt.
 2. The composition of claim 1, wherein the arginine ispresent in an amount of about 1.5 wt. % of the total composition weight.3. The composition of claim 1, wherein the salt of the basic amino acidis formed in situ in the formulation by neutralization of the basicamino acid with an acid or a salt of an acid.
 4. The composition ofclaim 1, wherein the salt of the basic amino acid is formed byneutralization of the basic amino acid to form a premix prior tocombination with the fluoride salt.
 5. The composition of claim 1,wherein the pH is between about 8.0 and about 10.0.
 6. The compositionof claim 1, wherein the precipitated calcium carbonate has a D₅₀ of3.5-7.0 microns, a D₉₀ of 7.0-14.5 microns and a D₁₀ of 0.6-1.7 microns.7. The composition of claim 1, wherein the precipitated calciumcarbonate in an amount of about 30 wt. % to about 50 wt. % of the totalcomposition weight.
 8. The composition of claim 1, wherein theprecipitated calcium carbonate (PCC) has an average particle size of 3.5to 7.0 microns and water absorption of greater than 15 g/100 g.
 9. Thecomposition of claim 1, wherein the oral care composition comprises: a.purified water from 40-45% by wt. b. precipitated calcium carbonate from35-45% by wt. c. glycerin at about 6% by wt. d. sodium lauryl sulfatefrom 4%-7% by wt. e. sodium monofluorophosphate from 0.50%-1.25% by wt.f. Sodium bicarbonate from 0.5%-1.50% by wt. g. Arginine from 1%-2% bywt. h. Polysaccharide gum from 0.1-0.4% by wt.
 10. A method comprisingapplying an effective amount of the oral care composition of claim 1, tothe oral cavity of a subject in need thereof, to: i. reduce or inhibitformation of dental caries, ii. reduce, repair or inhibit early enamellesions, e.g., as detected by quantitative light-induced fluorescence(QLF) or electrical caries measurement (ECM), iii. reduce or inhibitdemineralization and promote remineralization of the teeth, iv. reducehypersensitivity of the teeth, v. reduce or inhibit gingivitis, vi.promote healing of sores or cuts in the mouth, vii. reduce levels ofacid producing bacteria, viii. to increase relative levels ofarginolytic bacteria, ix. inhibit microbial biofilm formation in theoral cavity, x. raise and/or maintain plaque pH at levels of at least pH5.5 following sugar challenge, xi. reduce plaque accumulation, xii.treat, relieve or reduce dry mouth, xiii. clean the teeth and oralcavity, xiv. reduce erosion, xv. whiten teeth, xvi. immunize the teethagainst cariogenic bacteria; and/or xvii. promote systemic health. 11.The composition according to claim 1, wherein the composition is an oralcare composition in a form selected from: mouth rinse, toothpaste, toothgel, tooth powder, non-abrasive gel, mousse, foam, mouth spray, lozenge,oral tablet, dental implement, and chewing gum.